Hermann Muller (1955) - The Effect of Radiation and other Present Day Influences Upon the Human Genetic Constitution

To begin with, I would like to express my appreciation and my sincere gratitude to the administration of the town of Lindau and to the hosts of this meeting for presenting us scientists with the opportunity to take part in these five days of mutual intellectual fertilisation, to get to know each other at a personal level and to enjoy your endearing hospitality in this beautiful and interesting environment. Above all, it is an encouraging example particularly for Americans to see to what intellectual and cultural heights a town as small as Lindau can raise itself – and also what sacrifices it is willing to make for this development. And now, if you pardon me, I should like to return to my mother tongue, English. This is because I fear, or, in a certain sense, I indeed hope that my German is worse than my genetics. Each cell contains a great collection of thousands of different genes, arranged in line in the chromosomes. It is by the interactions of the chemical products of these genes that the composition and structure of every living thing is determined. Each gene reproduces itself exactly, forming a daughter gene just like itself before each cell division. Thus, the daughter cells and individuals of later generations have genes like those originally present. However, these genes are subject to rare ultramicroscopic chemical accidents called gene mutations that usually strike but one gene at a time. The mutant gene that resulting from a mutation thereafter produces daughter genes that have the mutant composition. Thus, descendants arise which have some abnormal characteristic. These characteristics are of many thousands of diverse kinds. Very rarely a mutant gene arises which happens to have an advantageous affect. This allows the descendents who inherited to multiply more than the other individuals in the population. Until finally individuals with that mutant gene become so numerous as to establish the new type as the normal type, replacing the old. This process continued step after step, constitutes evolution. However, since the mutations result from ultramicroscopic chemical accidents, a mutant gene is in more than 99% of cases detrimental. That is it produces some kind of harmful effect, some disturbance of function. The disturbance may be enough to kill with certainty any individual who has inherited a mutant gene of this kind, this same kind from both his parents. An individual whom we will call homozygous because he has inherited the same kind of gene from both. Such a mutant gene which kills with certainty is called a lethal. More often the effect is not fully lethal but only somewhat detrimental, giving rise to some risk of premature death or failure to reproduce but not a 100% certainty of it. Now in the great majority of cases an individual who receives a given mutant gene from one of his parents receives from the other parent a corresponding but unlike gene, one of the original normal type. He is said to be heterozygous in contrast to homozygous. In the heterozygous individual it is usually found that the normal gene is dominant, the mutant gene recessive. That is the normal gene usually has much more influence than the mutant gene in determining the characteristics of the individual. However, exact studies show that the mutant gene is seldom completely recessive. It does usually have some slight detrimental affect on the heterozygous individual, subjecting him to some risk of premature death or failure to reproduce. That is a risk of genetic extinction. This risk is commonly of the order of a few percent down to some small fraction of 1%. It is readily seen that if a mutant gene causes an average risk of extinction of, for instance 5%. That is a chance of 1 in 20 of dying off without leaving offspring like itself. This mutant gene will on the average pass down through about 20 generations before the line of decent containing this gene is extinguished. Because that risk will continue generation after generation until extinction does occur. And a 1/20th chance in each generation takes on the average 20 generations to reach its fruition. It is therefore said that the persistence, P of that particular gene is 20 generations. There is some reason to estimate that the average persistence of mutant genes in general may be something like 40. Although there are vast differences between mutant genes in this respect. That would mean the risk of the extinction in any one generation of 2½%. Observations on the frequency of certain mutant characteristics in man, supported by recent more exact observations on mice by Russell working at Oak Ridge indicate that any one given gene on the average, any one gene, undergoes one mutation of a given type per generation among 50,000 to 100,000 human germ cells. That is the mutation frequency for one gene which we call My. Haldane invented this terminology, the Greek letter My for mutation. My for one gene. Observations on the fruit fly drosophila show that there are all together at least 10,000 times as many different mutations occurring as those of a given type in a given gene altogether. Now since it is very likely that man is at least as complicated genetically as the fly drosophila, we must multiple our figure of one in 100,000 which to be conservative we assume for one type of mutation by at least 10,000 to get a minimum estimate for the total number of mutations arising in each generation in all genes together in human germ cells. That is one in 10 to one in 5 according to whether we take one in 100,000 or one in 50,000. Now every individual, each of us, arises from 2 germ cells, sperm and egg and therefore contains twice this number of newly arisen mutations. That is 2 in 10 to 4 in 10. This is per germ cell per generation of course. This means that among each 10 of us on the average there are 2 to 4 mutations which arose in the germ cells of our parents, even though our parents were given no irradiation or other special treatment. This then is the frequency of so called spontaneous mutation. Now far more frequent than the mutant genes that have newly arisen in the parental generation, the immediate parents are those with arose in earlier generations and have been handed down and which have not yet been eliminated from the population by causing death or failure to reproduce. The average frequency, F, of all the mutant genes present per individual of the population, for you and me, is easily calculated if we know My and P by simply multiplying them together. For example if My is 2 in 10, that is 2 new mutant genes arising among 10 individuals in each generation on the average and P is 40. That is each gene tends to persist for 40 generations on the average. Then an individual of any given generation must contain an average accumulation of as many mutations as have arisen over the past 40 generations. That is 40 times 2 over 10 or 8. This very rough estimate which I made 6 years ago happens to agree well with the figure 8 estimated a few months ago by Slatis in Montreal by a very different and more direct method. His method was based on the frequency with which definite homozygous abnormalities appeared among the children of marriages between cousins. This figure 8 by the way does not include most of the multitude of more or less superficial differences, sometimes conspicuous but very minor in the conduct of life whereby we commonly recognise one another. These minor differences probably arise seldom by mutation, yet become inordinately numerous because of the very high value of P, persistence, which they have. The figure 8 then includes the more major detrimental characteristics. We can’t draw an exact line of course. These characteristics, these 8 or more detrimental genes however, being nearly always heterozygous in us are only slightly developed and yet enough developed to give each one of us a pattern of idiosyncrasies. I think I’d like to make a diagram to give you a more graphic idea of this relationship. Suppose we have here some individuals of a population. They reproduce and form 10 more. This is a much simplified diagram. And of these 10, 2 have a new mutation, just arisen in the previous generation and that’s passed down. And it’s passed down for 4 generations because the persistence we suppose in this simplified diagram is 4. And the mutation frequency is 2 in 10. Then in the next generation there’ll be 2 more. And in the next 2 more and so on. And you can see that if we start with no mutations the number here is each generation, a vertical column. The number gradually rises until it becomes 8. Then it says there until mutation stops occurring. Of course in the big population it would keep on. And so it would become stable at 8. And F, if F is the number of mutations it will equal MP. But of course in our case P is 40, where did I slip up there, I didn’t want to represent 40 but only as a matter of fact 8, Here the average individual only has 4 out of 10. And if the persistence was 40, the average individual would himself contain 8. That’s alright, that makes that 8/10th for this case. And if we have 40 it becomes 8. Gives each of us 8. Now as the diagram shows each mutant gene must at last cause the extinction of its own line of decent. Not only the gene comes to an end but that individual and his descendents come to an end. And they’re replaced by others who are multiplying. And in that way that gene causes a frustrated life at that point, an unsuccessful life. Moreover, that gene caused a succession of slight disturbances in the intermediate generations before the final extinction. It is interesting to note that a slightly detrimental gene, one that persists for many generations, also causes one frustrated life, one unsuccessful life, just as a very detrimental gene does. Only it takes longer before it happens to do that. Moreover, the slightly detrimental gene, although on the average it causes each individual carrying it to suffer less, is handed down to a larger number of individuals. To a number of individuals which is the reciprocal of the amount of harm expressed in terms of the risk of extinction that it causes. And in this way the slightly detrimental gene does as much harm in the end as a fully detrimental gene, a lethal. Now although each of us may be handicapped very little by any one of these genes in heterozygous condition, the sum of all 8 of them causes a noticeable amount of disability ranging, varying in pattern from one of us to another. And felt more in our later years of course, we feel our disabilities. Altogether we see that the group of the 8 or more, or less genes gives us a risk of premature death of roughly 20% or 1 in 5. Greater than that which an ideal normal man who is of course non existent, would have. Now these numbers are of course only approximations to give you an idea of the order of magnitude. Besides, the frequency F which is called the equilibrium frequency exists only when conditions for gene elimination and for mutation frequency have remained stable for many generations. Because over many generations as many mutations must arise per generation as are eliminated giving us stable value of F. Just as in the law of mass action in chemistry, a stable amount of a substance depends upon the same amount being destroyed as produced. But if the mutation rate changes, this again is like the law of mass action in chemistry. As for example by the application of radiation or if the persistence changes because of environmental conditions that cause mutant genes to have a more or a less harmful affect than before. Then the product MP assumes a new value. That means that there will be a new equilibrium level of F if the new values of My and P continue long enough. But it will be a long time before this new equilibrium is attained. Theoretically it’s never reached. Thus in our diagram we see that with P equals 4, it will take 4 generations before this equilibrium number is attained. This keeps increasing for 4 generations, equal to P equals 4. The actual case is more complicated because P doesn’t have a fixed value. Some genes are a little more and some less, some are much more and so it’s spread out. With P equals 40 on the average it would take something like 40 generations or about 1,000 to 1,200 years in man to get near an equilibrium value of F. And after only 20 generations or 500 or 600 years the equilibrium would be only about half reached. Let’s now see how a given dose of ionising radiation would affect the population. Radiation induces mutations similar to the spontaneous ones. At a frequency that’s linearly proportional to the dose of ionising radiation received by the germ cells. In no matter how long or short a time that’s been delivered. Now Russell’s data on mice, the organism studied in this respect which is nearest to man, show that it would take about 40 R/units, 40 R of radiation to produce mutations at a frequency equal to the natural frequency. Since we have estimated the spontaneous mutation frequency to be 2 mutations per individual that is to be 2 mutations in each 10 individuals at a minimum estimate. Then a dose at 40R by adding 2 induced mutations to these 2 spontaneous ones would result in a total frequency of 8 mutations among 10 individuals. That is the rate would be doubled. Yet the mutant gene content of the individuals being 8 per individual to begin with would be raised only from 8 to 8.2. An increase of only 2½% by this 40R in the next generation. This effect on the population would ordinarily be too small to be noticed. In causing decreased vigour or decreased size or increased mortality, or morbidity or frequency of abnormalities. One must remember in this connection that the error of any mean value for such characteristics is very large. Not only because of the great genetic differences between the individuals of the population. But because environment too is a source of differences in the expression of their inherited traits. And because one often gets determinate differences in environment between 2 groups that are compared. This explains why even Hiroshima survivors who had been near the blast and who may have received several hundred roentgens showed no statistically significant increase in genetic defects among their children. However, the offspring of American radiologists who probably got about the same amount over their life of radiation as the people at Hiroshima near the blast did in the studies of Macht and Lawrence just published, show a statistically significant increase in abnormalities among their children. A small but significant increase. Yet even though they do not show statistically that mutant genes are produced and they do take their toll in the end of genetic extinctions. But because of the value of P being so large, this toll is spread out over more than 1,000 years and so it’s quite small in any one generation, relatively. Actually, the most damage is done in the first generation after exposure. Because gradually the mutant genes die out. Contrary to common opinion which holds that later generations would show more affect. How much damage would be done in the first generation we can find in this way. If 40R were received then you have .2 new extra additional mutations received per individual. But since the persistence, P is 40, only 1/40th of those will cause extinction in any one generation, for example in the first generation. And therefore only 1/40th of .2 or 1 in 200 meet with extinction. It means that 1 in 200, ½ of 1% of the individuals of the first generation are killed. In other words in the population of 100 million it would be 500,000 in the first generation. Spread out over all the generations you multiply it by 40 and you find that there were 20 million. There will have been 20 million extinctions in a population of 100 million. Moreover, those are only the extinctions, the disabilities found in intermediate generations will of course be far more numerous. And yet in spite of this the amount of deterioration in the population as a whole is relatively very little. The situation would be very different if a doubling of the mutation frequency were carried out repeatedly by irradiating the population in each generation for a period comparable with P, say 1,000 years. For in that case F would gradually creep upwards towards the new equilibrium value proportional to the doubled mutation frequency. And after 1,000 years or so F would have been changed from 8 to about 16 by the 40R received over these many generations. Along with this double mutation frequency there would be a corresponding increase in the amount of disability manifested among the individuals of the population. And in the frequency with which they met genetically occasioned extinction. It is possible that this situation unlike that caused by only a single generations doubled mutation frequency would really be ruinous to a human population. For in man a given rise in mutation frequency is more dangerous than in most species. For the very low rate of multiplication of man does not allow nearly as rapid a rate of elimination per generation of detrimental mutant genes as in most species. And under modern civilised conditions this multiplication rate is reduced much more still. While at the same time the pressure of natural selection for the time being at least, in modern times is greatly reduced through the artificial saving of lives. Under these circumstances a long continued doubling of the mutation frequency by something like 40R per generation might call for a higher rate of elimination than the population could tolerate. This would mean in the long run the continued deterioration of the population in its gene content. More and more accumulation of mutant genes. And at last its diminution in numbers until finally total extinction ensued. We do not at present however have nearly enough knowledge of the strength of the various factors to pass a quantitative judgement as to how high the critical mutation frequency would have to be and how low the levels of multiplication and selection to bring about this denouement. We can only see that danger lies in this direction and ask for further study of the whole matter. Let us now consider the effects of nuclear explosions. As for test explosions, test explosions at the rate at which these have been carried on over the past 4 years, over the past year. They have been estimated to cause an approximate doubling of the background radiation of about 1/10th R per year. The background radiation we estimate causes about 6 to 12% of the spontaneous mutations in man. The others come from chemical causes. Therefore, a doubling of the background radiation would cause a 6 to 12% rise in the mutation frequency. Although this if continued does mean a very large absolute number of mutations per generation in the whole world population. About a million extinctions per generation caused by the test explosions in the whole world if they were continued at this rate. Nevertheless, its effect relatively to the whole population, the whole mutant gene content is extremely small. Atomic warfare presents a much more serious picture. In regions remote from the explosions such as the southern hemisphere might be it has been reckoned by Rotblat and by Lapp in the May and June issue of the bulletin of the Atomic Scientists that a hydrogen uranium fission fusion fission bomb like the ones recently tested in the Pacific would deliver an effective dose of about .04R throughout the whole period of its radio active disintegration, many years. Thus 1,500 such bombs used in war would deliver about 60R. That is to regions remote from the immediate fall outs. And so would approximately double the mutation frequency of the immediately exposed generation. In the regions subject to the more immediate fall outs, pattern bombing could have resulted in practically all populace areas receiving several 1,000 roentgens of gamma radiation. Even persons well protected in shelters during the first week might subsequently be subjected to a protracted exposure fading only very slowly and adding up to some 2,500 roentgens. You can look up Lapp, the article I’ve already referred to for that. Moreover, this estimate fails to take into account the soft radiation, alpha and beta from inhaled and ingested materials which under some circumstances as yet insufficiently dealt with in open publications may become concentrated in the air, water or food and find fairly permanent lodgement in the body. And some of them may there become concentrated also. Now although 400 roentgens is the semi lethal dose, that’s killing half of its recipients if received within a short time. A much higher dose can be tolerated if spread out over a long period of time. Thus a large proportion of those who survive and reproduce such fall outs may have received a dose of some 1,000 to 1,500R or even more. This would cause a 12 to 40 times rise in the mutation frequency of that generation. Not 12 to 40% understand, 12 to 40 times. If the mutant gene content is already because of P being 40, about 40 times the spontaneous mutation frequency, then the artificially induced mutation frequency here by adding to the germ cells another contingent of mutation genes. In fact the detrimental effect would be considerably greater than that indicated by these figures because the newly added mutant genes unlike those being stored at an equilibrium level would not yet have been subjected to any selective elimination in favour of the less detrimental ones. It can be estimated that this circumstance might cause the total detrimental influence of the newly induced genes to be twice as strong for each one on the average. As for each of the old stored so to speak genes. Therefore the increase in detrimental affect caused by the fall outs would be between 60 and 200%. Owing to these circumstances, an effect would be produced by this exposure to this one generation similar to that of a doubled accumulation of genes such as we saw would follow from a doubled mutation frequency only after about 1,000 years of its continued repetition when a new equilibrium level of accumulation had been approximated. Thus offspring of the fall out survivors might have genetic ills, twice or even 3 times as burdensome as ours. Yet at the same time the material and social disruptions occasioned by the war would enormously reduce the ability of the population to cope with and to compensate for these ills by means of medicine and all the other artificial aids to living on which we have come to depend so largely today. The worst of the matter is that this enormously increased genetic load, even though produced by a rise of the mutation frequency lasting little more than one generation, would be by no means confined to just 1 or 2 generations. Here is where the inertia of mutant gene content which in the case of a moderately increased mutation frequency works to retard, to delay and spread out, and so to soften the impact of the produced mutations, now shows the reverse side of its nature, its extreme prolongation of the effect. That is the gene content is difficult to raise. But once raised it is equally resistant to being reduced. In consequence the situation will for centuries resemble that in which an equilibrium had been attained with a mutation frequency that had been long continued at a level 2 or 3 times as high as the present one. Supposing the average content of markedly detrimental genes per person to be only doubled from 8 to 16, it can be reckoned that more than 50% of the population would come to contain a number of these mutant genes. When we consider how much we of today are already troubled with ills of partly or wholly genetic origin, especially as we grow older, the prospect of so great an increase in them is far from reassuring. It is fortunate in the long run that sterility and death ensue beyond a chronically administered dosage level of 1 or 2,000 roentgens. Because the frequency of mutations received by the descendents of an exposed population is in this way prevented from rising much beyond the amount that we have just now considered. This being the case it is probable that the offspring of the survivors, even though so considerably weakened genetically, would nevertheless, some of them be able to struggle through and re-establish a population that could continue to survive. Yet supposing that the population is able to re-establish its stability of numbers within say a couple of centuries, what price would the later generations have to pay in terms of premature death and failure to reproduce caused by the induced mutations? If in accordance with the evidence previously given, 40R admitted to produce .2 newly arisen mutant genes per person, then 1,000R must on the average add 5 mutant genes to each person’s composition. All of these 5 genes must ultimately lead to genetic extinction in a subsequent generation. But if to be conservative we suppose that 2 to 3 genes on the average combine in causing extinction. By their synergistic action we reach the conclusion that in a population whose numbers remain stable after the first generation following the explosions, there will be about 2 cases of premature death of failure to reproduce occurring in subsequent generation or other. For each first generation offspring of an exposed individual. That is if there had been 100,000 first generation offspring, there’d be 200,000 subsequent deaths in sub generation. The same in terms of millions. If however the descendents multiply so as in a century or 2 to re-establish a population equal in number to the original population, then since the great majority of the extinctions occur in more remote generations their number will be multiplied along with the number of the whole population. And so the number of genetic deaths or extinctions will become approximately twice as large altogether as the number of persons constituting the re-established population size of any one generation. The future extinctions would in this situation be several times as numerous as the deaths that have occurred in the directly exposed generation. If 70 million people had been killed at the time of the explosions then something like let’s say 2 or 300 million will be killed in future generations. At the same time the people suffering from more or less ... Even though we admit it to being probably that mankind would ultimately revive, let us not make the all too common mistake of gauging whether or not any given or proposed exposure to radiation is genetically permissible merely by the criterion of whether or not humanity at large would be completely destroyed by it. The instigation of atomic war or indeed of any other form of war can hardly find a valid defence in the proposition. Even though true that it will probably not wipe out the whole of mankind. It is by the more exacting standard of whether individuals are harmed, not by the criterion of whether mankind in general will all be wiped out, that we should judge the propriety of our other present day and proposed practices that may affect the human genetic constitution. We have to consider in this connection for one thing, the amount of radiation which the population should be allowed to receive as a result of the peace time uses of atomic energy in polluting that derived from atomic waste. How much effort in convenience of money are we willing to expend in the avoidance of one genetic extinction, of one line of decent of a person. One frustrated and other partially frustrated lives, not to be seen ever by us. Will we accept the present official view that the permissible dose for industrially exposed personnel may be as high as .3R per week, that is 300R in 20 years. A dose which would lead such a worker to transmit somewhere between ½ and 1½ mutations per offspring conceived after that time. Exactly the same questions apply in medical practice. The United States public health survey conducted 3 years ago showed that at that time Americans were receiving a skin dose of radiation averaging about 2R per person per year from diagnostic examinations alone. Of course only a small part of this would have reached the germ cells. But if the relative frequencies of the different types and amounts of exposure were similar to those in studies recently carried out in British hospitals by Stanford and Vance, we may calculate from their data that the total germ cell dose to the Americans was about 1/30th of the total skin dose. That is in this case about .06R per person per year. This is about 12 times as much as the dose that had previously been estimated to reach the reproductive organs of the general population in England. However America is notoriously lighting the wave of the future in regard to the employment of x-rays. And it is still engaged in rapidly expanding their use while other countries are following as fast as they can. Now this dose of .06R per year, per person is of the same order of magnitude but twice as large as the annual dose received in the United States over the past 4 years, per year from all nuclear tests, explosions. It is my personal opinion that at the stage of international relations at which we have been during the past several years, these nuclear tests have been justified as warnings and as defensive preparations against totalitarianism. Although it is to be hoped that this stage is now about to become obsolete. On the contrary however I cannot find justification for the large doses received from medical irradiations. Which as I have just shown you are about equal or more in amount. For comparatively little thought in convenience or expense would be involved in the routine provision of shielding over the reproductive organs of individuals who may later reproduce. My experience is that when they ask for such a shield, in our country at least, they’re simply laughed at and it’s refused. And little thought or inconvenience in making many obvious and easy rearrangements of the irradiations so as to reduce the dose being received by the reproductive organs and other parts not being examined. I won’t go into the details of that, it’s very simple most of the radiologists as an investigation by Sonnenblick has shown hardly, they don’t know what dose they’re delivering at all, not one in 100 knew. Moreover the widespread present day procedures of intentional heavy irradiation of the ovaries to induce ovulation in infertile women and the heavy irradiation of the testes to provide an admittedly temporary means of avoiding pregnancies should hence forth be regarded as malpractice, in my opinion. We must remember that atomic tests and possibly atomic warfare may be dangers of our own turbulent times only. Whereas physicians will in some form always be with us. It is easier and better to establish salutary policies with regard to any given medical practice early than late in its development. If we continue neglectful of the genetic damage from medical irradiations, the dose received by the germ cells will tend to creep higher and higher and to be joined by a rising dose received from industrial applications of radiation and of the energy from radioactivity. For the industrial powers that be will tend to take their cue, their advice in such matters from the physicians as they have done, not from the biologists, even as the military and administrative powers that be do today. It should be our generation’s concern to take note of this situation and to make further efforts to start the expected age of radiation, if there is to be one, off in a rational way as regards protection from this insidious agent so as to avoid that permanent significant raising of the mutation frequency which in the course of ages could do even more genetic damage than an atomic war. But radiation is by no means the only agent capable of greatly increasing mutation frequency. Various organic substances such as the mustard gas groups. Some peroxides, epoxides, carbonates, triazine, ethanol sulphate, formaldehyde and so on can raise the mutation frequency about as much as radiation. The important practical question is to what extent may man be unknowingly raising his mutation frequency by the ingestion or inhalation of such substances or substances which after entering the body may induce or result in the formation of mutagens, that is, mutation producing substances that penetrate to the genes, the germ cells. Although some of the known mutagens such as the mustards would seldom be encountered in daily life under normal conditions, others such as some peroxides would enter the body more frequently or would even be manufactured there. In the later cases however there are often efficient means of destruction, channelization or disposal in the body. Such as catalase and the cytochromes that ordinarily greatly reduce the opportunity of these substances to attack the genes. Yet under certain circumstances, more especially with certain combination treatments these protective mechanisms may not work. As yet far too little is known of the extent to which our genes under modern conditions of exposure to unusual chemicals are being subjected to such mutagenic influences. Other large differences in the frequency of so called spontaneous mutations have been found in my studies on the mutation frequency characterising different stages in the germ cycle of drosophila. Moreover some evidence has been introduced by Haldane dealing with data of Mørch and others that the germ cells of older men have a much higher frequency of newly arisen mutant genes than those of young men. If this result, which has been found not to hold for the fruit fly drosophila should be confirmed for men, there’s some doubt about it. It might prove to be more damaging genetically for human population to have the habit of reproduction at a relatively advanced age than for its members to be regularly exposed to some 50R of ionising radiation in each generation. It’s evident from these varied examples that the problem of maintaining the integrity of the genetic constitution is a much wider one than that of avoiding the irradiation of the germ cells, since other influences may play a mutagenic role as great or greater. Now since F equals My P and P, the persistence is the reciprocal of the rate of elimination of mutant genes. It is evident that the rate of elimination is just as important as the mutation frequency in the determination of the human genetic constitution. If one prescribes some more distinctive term, one may say selected, than elimination, one may say selective elimination. Selective multiplication or simply selection. The importance of this factor is seen in the fact that the ancestors of men and mice, in them much the same mutations must have occurred in the original common ancestors, yet the different conditions of their existence. The ever more mousey living of the mouse progenitors and the manlier living of the pre-men caused a different group of genes to become selected from out of their common store. A very distinctive feature of the type of selection operating among human beings living under the conditions of our modern industrial civilisation is the tremendous saving of human lives that under primitive conditions would have been sacrificed. This is accomplished in part by medicine and sanitation, but also by the abundant and diverse artificial aids to living supplied by industry and widely disseminated through the operation of modern social practices. So small is now the proportion of those who die prematurely that it must be considerably below the proportion who would have to be eliminated in order to keep the rate of elimination of mutant genes equal to the rate of their origination by mutation. Surely less than 2 in 10 for elimination. We know in America the great majority live to 65, 70, 69 anyway for men, over 70 for women. In other words many of the saved lives must represent persons who under more primitive conditions would have died as a result of genetic disabilities. Moreover among those who survive there does not seem to be much selective influence in hindering the marriage and multiplication of the genetically less capable. In fact there are certain oppositely working tendencies. Therefore it is probably a considerable underestimate to say that a half of the detrimental genes that under primitive conditions would have met genetic extinction, today survive and are passed on. Calculating on the basis of this conservative estimate we find that in some 10 generations, 250 to 300 years, the genetic affect would have become much like that of applying 200 to 400 roentgen units all at once, as with the offspring of the most heavily exposed Hiroshima survivors. Of course as time goes on the rate of rise in accumulation towards a new equilibrium level of F falls off more and more from linearity until at last at equilibrium the curve is again flat. However in the situation we are considering the simultaneous advance of techniques would tend to raise the equilibrium level ever higher. And would thereby foster continued accumulation. In this way the passage of 1,000 years would be likely to result in the population as heavily loaded with mutant genes as though it were derived from the survivors of hydrogen uranium fission fusion fission bomb fallouts. And 2,000 years would continue the story until the system fell of its own weight or became reformed. The process just depicted is a slow invisible, secular one. Like the damage resulting from many generations of exposure to overdoses of diagnostic x-rays. Therefore it is much less likely to gain credence or even attention than the sensational process of being overdosed by the fallouts from bombs. This situation then ever more than that of the fallouts calls for basic education on the part of the public and the publicists before they will be willing to reshape their deep rooted attitudes and practices as required. It is necessary for humanity to realise that a species rises no higher genetically and stays no higher than the pressure of selection forces it to do. And to any relaxation of that pressure, it responds by sinking correspondingly. It will in fact take as much rope in sinking as we play out to it. The policy of saving all possible genetic defectives for reproduction must if continued eventually rob us of the very important benefits now enjoyed by which afflictions of generic origin today have their effects ameliorated and are often prevented from causing genetic extinction. The reason for this is evident as soon as we consider that when by artificial means a moderately detrimental gene is made less detrimental, its frequency will gradually creep upward toward a new equilibrium level at which it is finally being eliminated anyway. At the same rate as that at which it had been eliminated originally. Namely at the rate at which it arises per generation by mutation. This rate of elimination being once more just as high as before medicine began will at the same time reflect the fact that as much suffering and frustration will be existing in consequence of that detrimental gene as existed under primitive conditions. I explained how a slightly detrimental gene causes as much trouble in the end as a more detrimental one because it affects more individuals. Thus with all our medicine and other techniques we will be as badly off so far as many of the considerable group of ailments which, of genetic origin are concerned as when we started out. Not all genetic ills however would be simply made less detrimental, some of them would be made not detrimental at all under the circumstances of a highly artificial civilisation in the sense that they were unable to persist indefinitely and thus to become established as the new norm of our descendants. The number of these disabilities would increase in abundance up to such a level that no more of them could be supported and compensated for by the technical means available and by the resources of the social system. The burden of the individual cases up to that level would have become largely shifted from given individuals themselves to the whole community, through its social services, a form of insurance. Yet the total cost would be divided among all individuals. And that cost would keep on rising as far as it was allowed to rise. Ultimately then in that utopia of inferiority, in the direction of which we are at the moment headed, people would be spending all their leisure time in having their ailments nursed and as much of their working time as possible in providing the means whereby the ailments of people in general were cared for. Thus we should have reached the acme of the benefits of modern medicine, modern industrialisation and modern socialisation. But because of the secular, the very long time scale of evolutionary change and the inertia which retards changes in gene frequency this condition would come upon the world with such insensible slowness that, except for a few long haired cracks who took genetics seriously and perhaps some archaeologists, no one would be conscious of the transformation. If it were called to their attention they would be likely to rationalise it off as progress. It is hard to think of such a system not at length collapsing as people lost the capabilities and the incentives needed to keep it going. Such a collapse could not be into barbarism anymore however since the population would have become unable to survive primitive conditions. Thus a collapse at that stage would mean annihilation, unless there was still primitive people living in some corner of the world many in a preserve. But we’d be too humanitarian for that. There is however an alternative policy open to mankind and I am hopeful that before too late it will be adopted. This alternative policy by no means abandons modern techniques or recommends a return to the fabulous golden age of noble savages or even of rugged individualism. It makes use of all the science, skills and genuine arts we have to ameliorate, improve and ennoble human life. And so far as is consistent with its quality and well being to extend its quantity and range. Medicine, especially that of a far seeing, preventive and still better, that of a promoting kind, seeking actively to foster health, vigour and ability becomes on this policy more developed than ever. Persons who nevertheless have defects would certainly have been treated and compensated for it. So as to help them to lead useful, satisfying lives. But, and here is the crux of the matter, those who were relatively heavily loaded with genetic defects would consider it their obligation. Even if these defects had been largely counteracted by medicine to refrain, to keep from transmitting their genes. Except where such unusually valuable genes were also present in them that the gain for the descendents was likely to outweigh the loss. Through the adoption of such an attitude towards genetics and reproduction, an attitude seldom found as yet. And by this means only unless with Doctor Stanley and his colleagues we learn to artificially change the gene in the ways that we want to. Otherwise through this means only will it be possible for future generations indefinitely to maintain and to extend the benefits of medicine, of technology, of science and of civilisation in general. Anything else is to sell ourselves to the genius of decay for the satisfaction of a vain glorious desire for offspring who may for a few evanescent generations perpetuate our petty idiosyncrasies. It is true that for evolutionary changes in outlook, motivation and procedure are required before such a policy can be effective. The heart of these changes is the adoption of the viewpoint that whether or not a child should be produced in the given case or to be decided primarily according to the good of the next and succeeding generations and of the child himself, rather than for the edification or glorification of that child’s parents or ancestors. Nevertheless, no southern revolution in this respect is necessary or likely. It is sufficient for more and more persons gradually to come around to the more rational attitude. With the advance of realistic education, if as we must hope it will resume its advance despite its present decline in some of the most literate countries, there should come a better realisation of man’s place in the great sweep of evolution and of the risks and the opportunities genetic as well as non genetic which are increasingly opening to him. The tremendous realities of insensible, secular, long drawn out changes will be brought home to child and youth by means of vivid dramatised portraits. And if teaching does its duty that youth will become imbued with a will to act as a conscious agent of his species in its advance against outer and inner nature. Whether or not his personal genes for the most part like those of everyone else, are to go on, will then be a relatively minor matter to him. So long as he can foster the handing down of good genes, if possible better genes. He will also find gratification in helping to provide conditions where in these genes will be given the opportunity in their corporeal expressions of flowering ever more rich. It is evident from these considerations that the same change in view point that leads to the policy of voluntary elimination of detrimental genes would carry with it the recognition that there is no reason to stop short at the arrested norm of today. For all goods genetic or otherwise are relative. And so far as the genetic side of things is concerned, our own highest fulfilment is attained by enabling the next generation to receive the best possible genetic equipment. What the implementation of this view point involves by way of techniques on the one hand and of wisdom in regard to values on the other hand is too large a matter for treatment here. Nevertheless, certain points regarding the genetic objectives to be more immediately sought do deserve our present notice and when then I’m through, won’t take long. For one thing the trite assertion that one cannot recognise anything better than oneself or in imagination rise above oneself is merely a foolish vanity on the part of the self complacent. On the other hand men’s prejudices are so deep seethed. Men’s imaginations are so limited. And the world is so complex and full of pitfalls that it is important to guard against the setting up of far flung programs for the attainment of this or that peculiarity that happens to be in vogue. Such superficialities of mankind as colouration, size or features and so on are 2 disputations under modern conditions of too little importance for us to allow them to distract our attention from the more important objectives. Among these all around health and vigour, joy of life and longevity are unquestionable to be solved. Yet they are far from the supreme aims. For these aims we must search through the most rational and humane thought of those who have gone before us and integrated with the thought based on our present vantage point of knowledge and experience. In the light of such a survey I think it becomes clear that man’s paramount, his most important present requirements are on the one hand a deeper and more integrated understanding, better intelligence all around. And on the other hand a more heartfelt keener sympathy, that is a deeper fellow feeling leading to a stronger impulse to cooperation, more in a word of love. It is wishful thinking on the part of some psychologists to assert that these qualities result purely from condition or education. For although such factors certainly do play vital roles in the development of these traits, nevertheless homo sapiens wherever he occurs is relatively to other organisms both an intelligent and a cooperating animal, even though cooperating in only small groups. It is these 2 complex genetic characteristics working in combination, and only in combination, and serviced by the deftness of his hands which above all others have brought man to his present state. Moreover, there still exist great diverse and numerous genetic differences in the biological basis of these traits within any human population. Although our means of recognition of these genetic differences are today very faulty and tend to confound differences of genetic with those of environmental origin. Nevertheless, these means can be improved. And there’s work being done to improve it. Thus we can be enabled to recognise our betters. Yet even today our techniques are doubtless more accurate than the trials and errors whereby after all nature did manage to evolve us up to this point where we became effective in counteracting nature. Certainly then it would be possible if people once became aware of the genetic road that is open to them for a population to be brought into existence. Most of whose members were as highly developed in regard to the genetic basis of both intelligence and social behaviour as are those scattered individuals of today who now stand highest in either separate respect. This would be really lifting us a long way by our boot straps so to speak. Perhaps after this great advance had been made, men could begin to think constructively. Not only of ways of progressing still further in these same directions but also of the development of other accessory genetic features that would enhance their lives. If the fear of the misuse of nuclear energy awakens mankind, not only to the genetic dangers confronting him, but also to the genetic opportunities then this will have been the greatest peace time benefit that radioactivity could bestow upon us. Thank you. Applause.

Hermann Muller (1955)

The Effect of Radiation and other Present Day Influences Upon the Human Genetic Constitution

Hermann Muller (1955)

The Effect of Radiation and other Present Day Influences Upon the Human Genetic Constitution

Comment

For he Lindau meeting on chemistry in 1955, the physicist Werner Heisenberg had proposed that invitations should go out to all Nobel Laureates working on nuclear problems, such as radioactivity and ionising radiation. As a result, the meeting attracted Laureates from physics, chemistry and physiology or medicine. Because of this particular circumstance, the American biologist and geneticist Hermann Muller attended a Lindau meeting for the first and only time and gave a long and brilliant lecture (in English with a short polite introduction in German). The first part of the lecture is a pedagogical introduction to classical genetics and mutations. Two years earlier, Francis Crick and James Watson had discovered the double helix molecular structure of the gene and remarked that it should have implications for genetics. It is interesting to hear that Muller, at least as far as I can hear, did not refer to this at all in his unusually long lecture. The reason may be that it probably took quite some time before the molecular approach had an impact on the more classical geneticists. Instead of thus giving the young researchers and students in the audience an early warning of the revolution in molecular biology that would soon follow, Muller spends time and effort on a different but very important problem, that of atomic weapons, test explosions and radioactive fallout. As it is today, this was a topical question in 1955, the same year that the Russell-Einstein manifesto was made public in London (about one week before the Lindau meeting) and representatives of the four nuclear weapon carrying countries met at Lake Geneva to discuss disarmament (a few days after the Lindau meeting). Hermann Muller was one of the signatories of the Russell-Einstein Manifesto, which through dedicated work by Joseph Rotblat evolved into the Pugwash Conferences on Science and World Affairs (both jointly rewarded with the Peace Prize in 1995). Also Max Born, present at the Lindau meeting in 1955 (even though he didn’t give a lecture), was one of the signatories. So it is maybe not so surprising that the Nobel Laureates at the meeting wrote a statement of their own: The Lindau Manifesto. This was signed by 18 Nobel Laureates, two of whom were not present but were in telegraphic contact with Lindau. The manifesto was read to the meeting participants by Count Lennart Bernadotte at the closing ceremony on the island of Mainau. It is a short statement which not only asks for an abolishment of nuclear weapons, it also asks for an abolishment of war as a political instrument. It met with wide interest from news media and even though both nuclear weapons and wars are still around, the manifesto certainly helped put Lindau on the international map of the 1950’s!

Anders Bárány

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